Glutaric acidemia (GA-I) is an inherited disorder of amino acid metabolism that is characterized clinically by an extrapyramidal movement disorder in childhood and pathologically by neuronal loss and gliosis in the caudate and putamen. GA-I is caused by a deficiency of the enzyme glutaryl CoA dehydrogenase (GCDH) and is one of few movement disorders whose genetic basis is known. Over the past several years work in our center has led to the isolation of the GCDH protein and cloning of human, murine and porcine cDNAs. Work is ongoing to evaluate the phenotypic effects of specific mutations in the human gene in patients with GA-I. As a means to further the understanding of the pathophysiologic mechanisms involved in the development of the characteristic neuroanatomic and clinical features of GA-I we propose to generate a mouse model of this disease. Using the recently cloned murine cDNA we are now cloning the murine GCDH gene in preparation for creating a targeting vector to generate a null GCDH allele in embryonic stem (ES) cells via homologous recombination. These mutated ES cells will then be used to generate a line of mice that is heterozygous for the mutated GCDH allele. Subsequently, these heterozygous animals will be used to evaluate the developmental expression of GCDH using a marker gene which is incorporated into the targeting vector. Such analysis will allow for a correlation of the expression pattern of GCDH with the very characteristic neuropathology. The heterozygous animals will also be crossed to generate animals homozygous for the null GCDH allele. The homozygous animals will undergo extensive biochemical, behavioral and neurochemical evaluation in order to determine whether they are a good model of GA-I. If in fact they are a model of GA-I, these animals can be used to test specific hypothesis regarding pathophysiology and response to various treatment modalities.